Topical glycopyrrolate product

ABSTRACT

This invention relates to a convenient and safe product and method of applying glycopyrrolate topically in order to reduce excessive sweating in localized areas for those who suffer from this condition. This invention also relates to combining oral and topical delivery of glycopyrrolate to reduce excessive sweating and minimize side effects. This invention also relates to a convenient and safe product and method of applying glycopyrrolate topically to areas of compensatory sweating after endoscopic thoracic sympathectomy.

FIELD OF THE INVENTION

This invention relates to a convenient and safe product and method ofapplying glycopyrrolate topically in order to reduce excessive sweatingin localized areas for those who suffer from this condition. Thisinvention also relates to combining oral and topical delivery ofglycopyrrolate to reduce excessive sweating and minimize side effects.This invention also relates to a convenient and safe product and methodof applying glycopyrrolate topically to areas of compensatory sweatingafter endoscopic thoracic sympathectomy.

BACKGROUND OF THE INVENTION

Hays first reported on the topical application of glycopyrrolate forfacial sweating associated with eating (gustatory sweating). (1, 2)Subsequently others have reported on the use of topical glycopyrrolatefor hyperhidrosis and gustatory sweating. Oral glycopyrrolate has alsobeen used for hyperhidrosis. Glycopyrrolate does not cure any underlyingcauses of hyperhidrosis or gustatory sweating, but reduces or preventsthe resulting excessive sweating.

Use of glycopyrrolate as an anti-secretagogue in the treatment of pepticulcer disease commenced in Canada in 1961. It continues to be used as anantisialogogue in patients with drooling and as a premedication foranaesthesia to prevent excessive secretions.

Glycopyrrolate is a quaternary amine, which acts as an antimuscarinic,anticholinergic agent. It does not cross the blood brain barrier and itpenetrates biological membranes slowly and therefore, when giventopically leads to very few side effects.

As with all members of this class, glycopyrrolate should not be used bypeople with glaucoma or cardiac arrhythmias. Glycopyrrolate should alsonot be used by people with bladder obstruction, a rapid heart rate, anallergy to glycopyrrolate, or when pregnant or breast-feeding.

For most people sweating is a normal response to heat stress and isimportant in maintaining body temperature. However, in some individualssweating can be excessive and unrelated to heat stress. This excessivesweating can be embarrassing and can severely limit social activities.The areas typically involved in excessive perspiration are 1) faceincluding the neck and scalp 2) armpits 3) hands 4) back of the knees 5)feet 6) groin, and 7) in the case of compensatory sweating, the trunk.

Nerve impulses from the brain stimulate sweat glands and causeperspiration. Sometimes the nerves stimulate excessive sweatingunrelated to the normal process of temperature control.

The use of topical glycopyrrolate has been reported over the past 20years. Here is a table of clinical papers reporting use ofglycopyrrolate and the topical formulation used.

Treatment of Hyperhidrosis and Gustatory Sweating Author YearConcentration Formulation Notes Hay 1978 0.5 & 1.0% Solution and creamCotton applicator used to apply presentations solution. Hay 1982 0.5, 1& 2% Roll-on solution, Glycopyrrolate crystalized out distilled waterused. when concentrations above 2%. pH adjusted to 2.5 to 4.0 Fewpatients need to rub lotion into the skin to get better effects. Hay1982 2 & 4% HEB cream base Solution worked better than (Barnes- Hindcream. May 1989 0.5, & 2.0% 0.5 & 2.0% roll-on; almost all patientsobtained total 2.0% cream. Used Hays or partial relief. Placeboformulation. treatment yielded no response. Atkin 1996 0.50%cetamacrogol A Crushed Robinul ™ tablets mixed formulation cream baseinto cream Shaw 1997 0.50% cetamacrogol A formulation cream baseSeukeran 1998 2% cetamacrogol A Could not get cream into hairline.formulation cream base Cream and sweat mixture unacceptable. Seukeran1998 0.50% aqueous solution Worked well Urman 1999 0.50% Lotion in aroll-on dispenser

Here are the details from one of these papers. In a recent clinicaltrial (Shaw, J. E., C. A. Abbott, et al. (1997)) to determine if topicalglycopyrrolate is able to control diabetic gustatory sweating, theauthors found that topical glycopyrrolate is an acceptable safe andeffective treatment for diabetic gustatory sweating. A placebo orglycopyrrolate 0.5% cream was self administered by hand to the face andneck. A challenge test was administered, at baseline and at the end ofeach of the treatment periods. The sweat challenge test measures theamount of sweat produced on the forehead relative to reference sites onthe arm and the leg. Glycopyrrolate treated patients had a statisticallysignificant reduction in sweat production during the challenge test(p=0.008). Daily diary records indicated that topical glycopyrrolatetreatment resulted in a reduction in frequency and severity of gustatorysweating compared to the placebo treatment (p=0.004). One patient out of14 discontinued therapy because of a local skin reaction. No otheradverse effects were reported.

SUMMARY OF THE INVENTION

This invention relates to a pad containing an amount of glycopyrrolatein solution, for topical application of a therapeutically effectiveamount of glycopyrrolate, which is useful in reducing sweating inhumans. In an embodiment of this invention, the solution is a 5 to 66%ethanol solution and the amount of glycopyrrolate in solution is greaterthan 0.25% and not more than 6%, particularly 1%, 2% or 3%glycopyrrolate, or greater than 2.5 milligrams and not more than 60milligrams of glycopyrrolate.

In an embodiment of the invention the pad is a 75:25 rayon andpolypropylene pad containing about 1 ml of an about 2%glycopyrrolate/32% ethanol solution for topical application, which isuseful in reducing sweating in humans.

This invention also relates to a container containing multiple pads ofglycopyrrolate comprising a lid that is capable of being easily openedand closed and functions to prevent evaporation when closed.

This invention also relates to a use of a pad containing an amount ofglycopyrrolate in solution, for topical application of a therapeuticallyeffective amount of glycopyrrolate to any part of the human body onwhich the reduction of sweating is desired, with the exception of mucousmembranes.

This invention also relates to a use of a pad containing an amount ofglycopyrrolate in solution, for topical application of a therapeuticallyeffective amount of glycopyrrolate to any part of the human body onwhich the reduction of sweating is desired (with the exception of mucousmembranes) in combination with another oral and/or topical therapy forreduction of sweating.

This invention also relates to a method of preparing a container of padscontaining a 2% glycopyrrolate solution comprising:

-   -   Mixing 66.7 mL distilled water and 33.3 mL 95% ethanol together        to form an ethanol solution;    -   Adding 2 grams of glycopyrrolate powder to said ethanol solution        and stirring until completely dissolved;    -   Adjusting the pH level of said glycopyrrolate solution to 4.0        with hydrochloric acid;    -   Pouring 30 to 36 mL of said glycopyrrolate solution onto the top        pad of a container of 30 rayon/polypropylene pads; and    -   Covering the container with a resealable lid.

DESCRIPTION

Introduction

Excessive sweating can cause embarrassment in social situations and aneffective treatment is desirable. Glycopyrrolate has been used orallyand topically in the past to reduce excessive sweating. As indicatedabove, glycopyrrolate has been formulated for topical use as a cream,solution and roll-on, and has been applied using a cotton swab as anapplicator.

Using the previously available delivery methods, the topical applicationof glycopyrrolate can be messy and inconvenient. Oral treatment issimple to administer, however, oral treatment has systemic effects andthis causes increased side effects.

Accordingly, the inventors developed a new topical delivery product andmethod for glycopyrrolate, namely glycopyrrolate on pads. As well, theinventors combined the use of topical glycopyrrolate with oralglycopyrrolate to achieve maximum sweat control and minimal sideeffects.

Use of Invention

The topical application of glycopyrrolate is especially convenient forthose patients who have localized sweating of the face and hands. Thisinvention provides a convenient and safe method to apply glycopyrrolateto the skin in order to reduce excessive sweating in localized areas inthose who suffer from this condition. The present invention ofglycopyrrolate pads has benefits over previously used topicalglycopyrrolate as follows:

-   -   1. Ease of application;    -   2. Coverage of large flat surface such as face and neck (roll-on        applies narrow band);    -   3. Rubbing or massaging formulation into skin for better        efficacy (Hays 1982 showed this gave better efficacy in some        patients);    -   4. Applying approximately the same amount of medication at each        use;    -   5. A formulation that will allow application into the hairline        at the margins of the face since in gustatory sweating, facial        sweating extends into the hairline;    -   6. A rapidly drying non-greasy, residue free formulation that        permits the applications of cosmetics over top;    -   7. A hypoallergenic formulation containing no known allergens,        unless a preservation agent (antibacterial or chemical        stabilizer) is added, as may be required for commercial        formulations; and    -   8. A formulation that can be prepared in a wide range of        strengths to accommodate the variability of glycopyrrolate        absorption between different individuals; (Hays 1982, Rautakorpi        1998, provide evidence in their clinical paper on variable        absorption)    -   9. Convenient to use on the spot before certain events, for        example to reduce sweating on the palms to enhance performance        in situations such as golf or baseball etc, and to reduce        sweating in situations such as business presentations and        performing arts.

A surgical procedure called endoscopic thoracic sympathectomy (ETS), thecutting or clipping of fibers of the sympathetic nervous system, is alsoused to treat the condition of excessive sweating. One of the sideeffects of this procedure is compensatory sweating in adjacent areas notaffected by the surgical procedure. The present invention provides aconvenient and safe method of applying glycopyrrolate topically forthose patients with areas of compensatory sweating after endoscopicthoracic sympathectomy.

For those with excessive sweating over a very large body surface areaand severe sweating in localized areas such as the hands, feet and face,a combination of oral and topical delivery of glycopyrrolate providesthe best balance of sweat control and minimizing side effects. Thisinvention also relates to combining oral and topical delivery ofglycopyrrolate to reduce excessive sweating and minimize side effects.

Oral glycopyrrolate reduces excessive sweating, but in some patientslocalized problem areas e.g. hands or feet still remain. To get completecontrol the patient may not wish to increase the oral dose because thenthe side effects become intolerable. Topical glycopyrrolate appliedlocally to the problem spots improves the over all control ofhyperhidrosis. Because of its local application, it does not result inadditional side effects. Use of the invention can also be combined withother forms of topical glycopyrrolate, such as, glycopyrrolate in gel orcream form or a metered spray of a solution of glycopyrrolate.

Some patients have excessive sweating of the hands and trunk. (There areother combinations such as face, hands and trunk or hands and feet etc.)The hands, face, feet and axilla are usually worse than the trunk.Topical application works well for the local areas (hands, face, feet,axilla). But, areas such as the back may not be as accessible forself-application. If the surface area is too difficult or too large tocover with the topical product, the addition of an oral preparationhelps to treat hyperhidrosis more effectively than topical alone.

Finally, the topical glycopyrrolate invention may be used as anantiperspirant for individuals who experience ordinary sweating. Suchuse may be over the body, but it is particularly effective on theunderarms. Sweating is a normal body response and use on only theunderarms is recommended for those who experience ordinary sweating. Inthis way, the body's normal sweat production is not impeded anywhere butthe underarm and potential side effects are minimized.

The topical glycopyrrolate invention may incorporate perfumes, scents,preservation agents, moisturizers and the like, as are found in underarmdeodorants, provided that such additives do not compromise theeffectiveness of the glycopyrrolate.

Development of Invention

Formulations Examined

In order to provide an improved topical formulation, a water-basedformulation was desired. Glycopyrrolate dissolves readily in water.However, alcohol was added to the formulation to improve the speed ofdrying. Glycopyrrolate also dissolves readily in alcohol. Some testedformulations and results were as follows:

-   -   1. A 100% distilled water formulation was too slow in drying        when applied to the skin    -   2. A mixture of 33.3% distilled water and 66.7% of 95% ethanol,        evaporated rapidly but caused excessive drying. A bitter tasting        residue was left on the skin.    -   3. A mixture of 66.7% distilled water and 33.3% of 95% ethanol        dried faster than 100% distilled water but did not cause the        drying associated with the solution containing 66.7% of 95%        ethanol.

A solution of 66.7% distilled water and 33.3% of 95% ethanol was chosento deliver the glycopyrrolate. However, any solution which meets thecriteria of dissolving glycopyrrolate, being absorbed by an applicationpad, and quick drying without causing harm to the skin, can be used.

A concentration of glycopyrrolate greater than 0.1% is desirable since0.1% has been shown to be ineffective (Hays 1978). A 1% glycopyrrolatesolution was initially chosen for testing purposes. However, the rangeof glycopyrrolate can vary to meet the needs of the patient. The upperlimit could be at least as high as 6%, although mild side effects beginto present themselves after 4% (Hays 1978).

Preparation of 100 mL Solution of 1% Glycopyrrolate

A 1% glycopyrrolate solution was made by dissolving glycopyrrolatepowder in the 66.7 mL distilled water and 33.3 mL of 95% ethanolsolution.

Take water 66.7 mL

Add 95% ethanol 33.3 mL

Adjust pH to 4.0 (range 3.5 to 4.5) with a few drops of hydrochloricacid

Add 1 gram of glycopyrrolate stir until glycopyrrolate completelydissolved.

To make 2% solution add 2 gram glycopyrrolate instead of 1 gram etc.

The resulting solution of glycopyrrolate contains approximately 31.635%of ethanol. To avoid skin irritation, the pH of the formulation shouldbe close to that of the skin (pH 5.5). For the chosen 66.7%/33.3%distilled water/95% ethanol solution, the pH level was adjusted to 4.0with hydrochloric acid. The pH of 4.0 was chosen for stability of thesolution and to be as close to the pH of the skin (pH 5.5) as possible.

Application Pads Tested

The inventors discovered that glycopyrrolate could be deliveredeffectively using pads. The patient could easily and quickly apply theglycopyrrolate with a pad, which allowed the glycopyrrolate to bemassaged into the skin for improved results.

Cotton Cosmetic Pads

Here is the experiment conducted to determine the absorbency of cottoncosmetic pads.

Calculated amount of Weight of glycopyrrolate Dry weight of Wet weightof solution (assuming a Solution pad in grams pad absorbed 1% solutionWater 0.53 7.98 7.4 74 mg

These cotton cosmetic pads absorbed too much liquid making it difficultto control the application of the solution to the skin.

75% Rayon/25% Polypropylene Pads

Here is the experiment to determine the absorbency ofrayon/polypropylene pads, using the brand of Kleentest™ #9807 2.125diameter pads, comprised of 75% rayon and 25% polypropylene by weight.

Calculated amount of Average weight glycopyrrolate Average dry Averagewet of solution (assume 1% Solution weight (N = 10) weight (N = 10)absorbed (N = 10) solution) Water 0.196 1.393 1.197 11.9 mg 33.3% 95%0.192 1.219 1.027 10.3 mg Ethanol/66.7% Water 66.7% 95% 0.195 1.0340.839  8.4 mg ethanol/33.3% Water

These pads hold about 1 mL of liquid, are easy to apply to skin, and donot drip.

These pads impregnated with 1% glycopyrrolate solution of 66.7%/33.7%distilled water/95% ethanol contain about 10 mg of glycopyrrolate.

Variability in Pad Content Due to Stacking

The effectiveness of the glycopyrrolate solution on a pad also dependson whether the invention can be delivered to the patient for use.Several pads must be packaged in such a way that each individual paddelivers a desirable amount of glycopyrrolate.

The brand of Kleentest™ #9807 2.125 diameter pads are packaged forconsumer use in stacks of 30. Tests were conducted to determine whichsolution would give the best content uniformity in each pad from top ofthe stack to the bottom of the stack. A 1% solution was desired from theabove experiment.

The following experiment was conducted to determine if a consistentamount of glycopyrrolate was delivered per pad. Thirty to thirty-six mlof solution were added to ajar containing a stack of 30 of the brand ofKleentest™#9807 2.125 diameter pads. The average weight of the top sixpads was compared to the bottom 6 pads.

33.3% 95% Ethanol/ 66.7% 95% Ethanol/ Solution Water 66.7% Water 33.3%Water Av Net Wt Top 6 1.08 g 0.95 0.84 Av Net Wt 1.31 g 1.11 0.9 Bottom6 Difference 18% 15% 7%

The 66.7% 95% ethanol/33.3% water solution yields the smallest percentvariation from the average of the top 6 pads to the average of thebottom 6 pads. Increasing the water content to 66.7 and 100% increasesthe percent variation from 15% to 18%, respectively.

Preferred Invention of Glycopyrrolate on Pads

Other pads may be used as effectively if they meet the followingcriteria:

-   -   1. Pads made of a material able to hold about 1 mL of solution.    -   2. Solution containing from 0.25% to 6% glycopyrrolate.    -   3. Aqueous solution having an ethanol content greater than 5%        and less than 66%.    -   4. May also contain suitable preservatives, anti-fungals,        anti-bacterials and perfumes.        Use of Glycopyrrolate Pads

Take one pad and apply to the affected area once daily. If required asecond pad may be used for large surface areas.

Directions for using on face, hands, feet or armpits:

-   -   1. Remove a single pad from the jar.    -   2. Wipe affected area as desired.    -   3. Apply any cosmetics or creams only after the applied liquid        has dried.    -   4. Do not wash the treated area for at least 4 hours.    -   5. Avoid applying to mouth, eyes or mucous membranes. Contact        lens users: Insert contact lens before handling glycopyrrolate        pads or wash hands thoroughly before inserting lens.    -   6. Do not apply to cut or broken skin.    -   7. Discontinue use if rash or skin irritation develops.    -   8. Keep product away from children and pets.    -   9. Close container firmly after use to prevent evaporation.        Protect from heat.

EXAMPLES OF PATIENT RESPONSES TO GLYCOPYRROLATE PADS

The following examples show how the invention has worked for individualpatients, that is, delivering a therapeutically effective amount ofglycopyrrolate to reduce sweating, and how it can be adjusted for anypatient. For instance, if a patient is finding that the topical pads ofglycopyrrolate of the invention provide acceptable reduction in sweatingbut experiences side effects such as dry mouth, the strength of theglycopyrrolate in solution can be reduced to provide the best resultswithout side effects. Conversely, if sweating has not been reduced toacceptable levels, the strength of the glycopyrrolate in solution can beincreased.

Topically applied glycopyrrolate penetrates the skin over the sweatglands and acts as a shield preventing over-stimulation of the sweatglands. The effectiveness of the topical glycopyrrolate inventiondepends on the amount of nerve stimulation each individual brainproduces, the thickness of the skin over the sweat glands and theconcentration of glycopyrrolate. Most patients enjoy effective controlof sweating using the regular strength of 2% glycopyrrolate, however,personalized strength pads can be prepared to maximize the benefit fromthe treatment.

Generally topical glycopyrrolate should be made in the range of a 0.25%to 6% solution to deal with individual variability in penetration ofbiological membranes.

-   -   1. A 35 year old, male patient with excessive forehead and groin        sweating resulting in a facial rash and fungal infection was        advised to try the invention. The patient was started on a 1%        pad. After 2 weeks the patient reported that the glycopyrrolate        pads had worked so well that they had changed his life. His        facial and groin sweating had improved markedly and as a result        the chronic fungal infection of his groin and constant facial        rash had both improved. He was able to participate in social        situations that previously would have made him feel very        uncomfortable. The patient experienced no side effects while        using the 1% strength glycopyrrolate pads. The patient wished to        reduce his residual sweating. The patient is now using used 1.5%        strength glycopyrrolate pads and has obtained satisfactory        control of his sweating. He has not experienced any side        effects.    -   2. A 50 year old, male patient with excessive facial sweating        was searching for an alternative to oral therapy. The patient        had been taking up to 6, 15 mg capsules per day of        propanthaline, an oral anticholinergic. The patient was started        on 1% strength glycopyrrolate pads then moved to 2% strength        glycopyrrolate pads and finally 3% strength glycopyrrolate pads.        The 3% strength glycopyrrolate pads gave the patient almost        complete control of his facial sweating. The patient did not        experience any side effects while using 3% strength        glycopyrrolate pads. The patient only occasionally uses oral        propantheline.    -   3. A 40 year old male, suffering from excessive facial and scalp        sweating began using 1% strength glycopyrrolate pads on his        face. He was able to control his facial sweating. At the time of        re-ordering the 1% strength glycopyrrolate pads, he asked if        there was a more efficient manner for him to apply the        medication to the top and back of his scalp. The pad was not        allowing him to penetrate his strands of hair to apply the        medication directly to his scalp. He was provided with a 1%        solution of glycopyrrolate in water and ethanol in a metered        spray container. The patient uses the spray to apply the        glycopyrrolate solution to his scalp. The 1% glycopyrrolate        solution in a metered spray bottle was able to satisfactorily        reduce his scalp sweating. The patient also uses 1% strength        glycopyrrolate pads to control his facial flushing. The patient        has not experienced any side effects with the topical        application of glycopyrrolate.

Bibliography

-   1. Hays, L. L. (1978). “The Frey syndrome: a review and double blind    evaluation of the topical use of a new anticholinergic agent.”    Laryngoscope 88(11): 1796–824.-   2. Hays, L. L., A. J. Novack, et al. (1982). “The Frey syndrome: a    simple, effective treatment.” Otolaryngol Head Neck Surg 90(4):    419–25.-   3. Abell, E. and K. Morgan (1974). “The treatment of idiopathic    hyperhidrosis by glycopyrronium bromide and tap water    iontophoresis.” Br J Dermatol 91(1): 87–91.-   4. Ali-Melkkila, T., T. Kaila, et al. (1989). “Glycopyrrolate:    pharmacokinetics and some pharmacodynamic findings.” Acta    Anaesthesiol Scand 33(6): 513–7.-   5. Atkin, S. L. and P. M. Brown (1996). “Treatment of diabetic    gustatory sweating with topical glycopyrrolate cream.” Diabet Med    13(5): 493–4.-   6. Berrios, R. J. and P. D. Quinn (1986). “Frey's syndrome:    complication after orthognathic surgery.” Int J Adult Orthodon    Orthognath Surg 1(3): 219–24.-   7. Bronshvag, M. M. (1978). “Spectrum of gustatory sweating, with    especial reference to its presence in diabetics with autonomic    neuropathy.” Am J Clin Nutr 31(2): 307–9.-   8. May, J. S. and W. F. McGuirt (1989). “Frey's syndrome: treatment    with topical glycopyrrolate.” Head Neck 11(1): 85–9.-   9. Rautakorpi, P., T. Manner, et al. (1998). “Pharmacokinetics and    oral bioavailability of glycopyrrolate in children.” Pharmacol    Toxicol 83(3): 132–4.-   10. Seukeran, D. C. and A. S. Highet (1998). “The use of topical    glycopyrrolate in the treatment of hyperhidrosis.” Clin Exp Dermatol    23(5): 204–5.-   11. Shaw, J. E., C. A. Abbott, et al. (1997). “A randomised    controlled trial of topical glycopyrrolate, the first specific    treatment for diabetic gustatory sweating.” Diabetologia 40(3):    299–301.-   12. Sheehy, T. W. (1991). “Diabetic gustatory sweating.” Am J    Gastroenterol 86(10): 1514–7.-   13. Stern, L. M. (1997). “Preliminary study of glycopyrrolate in the    management of drooling.” J Paediatr Child Health 33(1): 52–4.-   14. Stuart, D. D. (1978). “Diabetic gustatory sweating.” Ann Intern    Med 89(2): 223–4.-   15. Urman, J. D. and A. M. Bobrove (1999). “Diabetic gustatory    sweating successfully treated with topical glycopyrrolate: report of    a case and review of the literature.” Arch Intern Med 159(8): 877–8.

1. A method of preparing a container of pads containing a 2%glycopyrrolate solution comprising: a. Mixing 66.7 mL distilled waterand 33.3 mL 95% ethanol together to form an ethanol solution; b. Adding2 grams of glycopyrrolate powder to said ethanol solution and stirringuntil completely dissolved; c. Adjusting the pH level of saidglycopyrrolate solution to 4.0 with hydrochloric acid; d. Pouring 30 to36mL of said glycopyrrolate solution onto the top pad of a container of30 rayon/polypropylene pads; and e. Covering the container with aresealable lid.